16-acetyl pregnane derivatives



United States Patent O 3,189,629 leS-ACETYL PREGNANE DERIVATIVE Pierre (Irabh, Mexieo ility, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed Sept. 5, 1962, Ser. No. 221,431 4 Claims. (Cl. 260-3974) The present invention relates to novel cyclopentanophenanthrene derivatives and to a process for the production thereof; 7

More particularly the present invention relates to novel 16-acetyl-pregnane derivatives.

The novel compounds or" the present invention, which are progestational type agents with a high anti-ovulatory activity and also anti-estrogenic and anti-androgenic agents, are represented by the following formulae:

/ "(Z-CH3 I;

r s k k C Ha I V CHOH I: I on In the above formulae Y represents a double bond or a saturated linkage, each between -5 and C-6; and Z represents a double bond or a saturated linkage, each between C-4 and C-5.

t tiOn are prepared by the process illustrated by 'ing equationz' 3,183,529 Patented June 15, 2935 The novel l7fi-pregnane derivatives of the present inven tion are prepared by the process illustrated as follows:

Inthe above formulae Y and Z have the sametmeaning as previously defined.

In practicing .the process outlined above the starting 16a-cyano-A -pregnene-35,2OB-diol (1) upon treatment (III) with'excess methyl magnesium iodide, in toluene-ether solution preferably at reflux temperature for a period of time of the order of 22 hours, followed by acid hydrolysis, yields 16u-acetyl-A -pregnene35,20fl-diol (H: Y=double b'ond) ,'which is hydrogenated in the presence of a suitable catalyst, such as platinum oxide, to give 16a-acetyl-allopregnane-3B,20fi-diol (II: Y=saturated linkage). The above 35,20,8-diols, upon treatment under conventional Oppenauer conditions, yield the corresponding 16u-acetyl- 3,20-dione derivatives (III).

The novel 17 a-pregnane derivatives of the present inventhe follow- CH3 CH HOAc HOH m got- Intheabove formulae Y'and Z have the same meaning .ias previously described and .Ac represents "the..acetyl radical. V

In practicing the process just outlined the starting 1615'- A carboxy-AF-l7e-pregnene-3fi,2t),B-diol-diacetate (IVJupon presence of a suitable catalyst, such as palladium-oncharcoal, yields 16B-acetyl l7u-allopregnane-3films-diol' (V: Y=saturated linkage).

The 16/3 acetyl-3/3;20,8-diol derivatives (V) upon con ventional Oppenauer oxidation afford the corresponding 16B-acetyl-3,20-dione derivatives (VI).

The following specific examples serve to illustrate but are not intended to limit the scope of the presentinvention:

Example I A A solution of 6 g. of. 16a-cyano-A -pregnene-3fl,20fl- V diol (Mazur et al., Tetrahedron, 7, 130 [1959]), in 700 cc. of toluene Was heated to the boiling point and 50 cc.

of solvent were-allowedto distil ofi. Thereafter were added 200 cc. of a 4 N ethereal solution of methyl magnesium iodide and the resulting mixture was allowed to reflux for 22 hours under anhydrous conditions, then it was ice-cooled, water was added thereto, and the organic layer-was washed with 5%. aqueous hydrochloric acid and then with water. The moist organicphase :was dried over anhydrous sodium sulfate and evaporated todryness.

The residue was treated.-with a :Girard' T solution and after'usual work up the iketonicir'action yielded 116atate (1.: Rome, Tetrahedron, 3,37 [1958] were dissolved -.in.f60. cc. or anhydrous benzeneand cc.;lof .the; solvent were then allowed to 'distilofi. The resulting solution .was cooled and lO cc, of thionyl' chloride were added. 'The reaction mixture was refluxed for 2 hours, and thereafter evaporated to dryness, thus .afiording the diacetateof AZ.

' -.The .same procedure Was applied The latter was dissolved in 30 cc. of benzene,..and;the

tion prepared previously by: mixing 15 cc. of a 4 N ether solution of methyl magnesium bromide with cc. of benzene, then slowly and withstirringwith 10 g. of anhydrous cadmium chloride, and allowing the resulting re- 1 resulting solution was added to a methyl cadmiumsolu- .50

agent solution to stand at room temperature. for 30 .minutes. .The acylchloride-methyhcadmium mixture .was

refluxed for 4 hours. After cooling there was added dilute hydrochloric acid, the organic layer was separated, I

Washed with water, dried andevaporatedto dryness. The residue was treated with Girard T reagent and upon usual work up the ket'onic fraction afiorded 16fi-acetyl-A -1'lqpregnene- SEZOB-diOI. V

' Example III {A solutionof 2.0 g. .of 16a-acetyl-A -pregnene-313,20,8-. diol in 100 cc; of ethyl acetate was'shaken with 100 mg; of 5%, palladium-on charcoal catalyst in .a hydrogen atmosphere until. the gas. uptake corresponded to re fmol.

The catalyst 'was filtered oft and't'h'e' filtratecvaporated to dryness. Recrystallization .from acetone-hexane afforded 16a-acetyl-allopregnane-3'eg20e diol. i

A solution of 1 g; of 16u-acetyl-A pregnene 35,205- diol in cc. of toluene and 20 cc. of cyclohexanone was dried by distilling oil 310 cc. of the solvent. A solution of 1 g; of aluminum isopropoxide dissolved in7 cc. of anhydroustoluene Wasthen added and the mixture was refluxed for 45 minutes; 4 cc. of acetic acid were added and the solvents removed by'steam distillation. The product was extracted several. tin1es. with ethyl acetate and I the organic extracts Washed with 5% hydrochloric acid solution, water 10% sodium carbonate solution and water' until neutral, dried over. anhydroussodium sulfate and evaporated to dryness. Crystallization. from acetonehexane afforded.l6m-acetyl-A -pregnene-3,20-dione.,

When applying the 'above procedure to;16 8-acetyl-A 1 17a-pregnene 35,205 diol, 16a-acetyl-allopregnanep,

ZOB-diohand 16B -acetyl 17a-allopregnane-3e,20p diol, there were respectively obtained: 16fl-acetyl-A -17 u-pregnene-.3,20-dione,' 16u-acetyl-allopregnane-3,20-dione, and 16fl-acetyl-17u-allopregnane-3,2(l-dione. 1

' Iclaim: V

. 16m-acetyl-A -pregnene313,20 8-diol.

. 16B-acetyl-A -17u-pregnene-3B,20}3-diol.

. 16a-acetyl-allopregnane 3,20,8;diol.

. 16fi-acetyl-17a-all0pregnene 3 6,20B-di0l. V

References Cited by the Examiner UNITED. STATES PATENTS 3,121,101 2/64 Daase et 1. 2603 97.3

LEWIS oor'rs, PrimdryExaminer.

M, L EBI E mine e 

1. 16A-ACETYL-$5-PREGNENE-3B,20B-DIOL. 